Genetic Variant NM_003616.3:c.585C>G (chr14-39128333-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003616.3(GEMIN2):c.585C>G(p.Asp195Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,411,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D195G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

GEMIN2
NM_003616.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0580

Publications

0 publications found

Variant links:

Genes affected

GEMIN2 (HGNC:10884): (gem nuclear organelle associated protein 2) This gene encodes one of the proteins found in the SMN complex, which consists of several gemin proteins and the protein known as the survival of motor neuron protein. The SMN complex is localized to a subnuclear compartment called gems (gemini of coiled bodies) and is required for assembly of spliceosomal snRNPs and for pre-mRNA splicing. This protein interacts directly with the survival of motor neuron protein and it is required for formation of the SMN complex. A knockout mouse targeting the mouse homolog of this gene exhibited disrupted snRNP assembly and motor neuron degeneration. [provided by RefSeq, Aug 2011]

GEMIN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.096943885).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003616.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GEMIN2	NM_003616.3	MANE Select	c.585C>G	p.Asp195Glu	missense	Exon 7 of 10	NP_003607.2	O14893-5
GEMIN2	NM_001009182.2		c.540C>G	p.Asp180Glu	missense	Exon 6 of 9	NP_001009182.2	A0A8J9FJK1
GEMIN2	NM_001009183.2		c.585C>G	p.Asp195Glu	missense	Exon 7 of 9	NP_001009183.2	A0A8J9FN78

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GEMIN2	ENST00000308317.12	TSL:1 MANE Select	c.585C>G	p.Asp195Glu	missense	Exon 7 of 10	ENSP00000308533.7	O14893-5
GEMIN2	ENST00000250379.13	TSL:1	c.540C>G	p.Asp180Glu	missense	Exon 6 of 9	ENSP00000250379.9	A0A8J9FJK1
GEMIN2	ENST00000396249.7	TSL:1	c.585C>G	p.Asp195Glu	missense	Exon 7 of 9	ENSP00000379548.3	A0A8J9FN78

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000213

AC:

AN:

1411006

Hom.:

Cov.:

AF XY:

0.00000426

AC XY:

AN XY:

704932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32124

American (AMR)

AF:

0.00

AC:

AN:

42866

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25760

East Asian (EAS)

AF:

0.00

AC:

AN:

39422

South Asian (SAS)

AF:

0.00

AC:

AN:

83486

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51174

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5630

European-Non Finnish (NFE)

AF:

0.00000280

AC:

AN:

1071834

Other (OTH)

AF:

0.00

AC:

AN:

58710

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.039

Eigen

Benign

0.0081

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.79

M_CAP

Benign

0.0024

MetaRNN

Benign

0.097

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.095

PhyloP100

0.058

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.020

REVEL

Benign

0.10

Sift

Benign

0.65

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.18

MutPred

0.31

Gain of catalytic residue at L211 (P = 0.0403)

MVP

0.60

MPC

0.14

ClinPred

0.59

GERP RS

4.0

Varity_R

0.30

gMVP

0.052

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over